Hepatocyte growth factor (HGF), also known as scatter factor, is a multi-functional growth factor that enhances transformation and tumor development by inducing mitogenesis and cell motility. Further, HGF promotes metastasis by stimulating cell motility and invasion through various signaling pathways. In order to produce cellular effects, HGF must bind to its receptor, c-Met, a receptor tyrosine kinase. c-Met, a widely expressed heterodimeric protein comprising of a 50 kilodalton (kDa) α-subunit and a 145 kDa alpha-subunit (Maggiora et al., J. Cell Physiol., 173:183-186, 1997), is overexpressed in a significant percentage of human cancers and is amplified during the transition between primary tumors and metastasis. The various cancers in which c-Met overexpression is implicated include, but are not limited to, gastric adenocarcinoma, renal cancer, small cell lung carcinoma, colorectal cancer, prostate cancer, brain cancer, liver cancer, pancreatic cancer, and breast cancer. c-Met is also implicated in atherosclerosis and lung fibrosis.
Drug-induced cardiac QT prolongation has recently been recognized to cause adverse or fatal side-effects in many clinical settings. The cardiac potassium channel hERG (human ether-a-go-go-related gene) encodes the α-subunit of the rapid delayed rectifier current IKr in the heart, which contributes prominently to terminal repolarization in human ventricular myocytes. See Dennis et al., Biochemical Society Transactions 35(5):1060-1063 (2007). It has been shown that inhibition of hERG potassium channel can lead to a prolongation of the QT interval, widely considered a critical risk factor for torsades de pointes (TdP) arrhythmia. Thus, overcoming hERG binding has become a major hurdle in drug development.
In addition to an awareness of the possibility of drug-induced QT prolongation, the metabolism of pharmacological agents by cytochrome P450 activity is also important, particularly in therapies that may involve a combination of such agents. The cytochrome P450 enzymes catalyze the oxidation of many therapeutic compounds and have an important role in the extent and duration of drug effects, by catabolizing drugs to inactive metabolites or by bio-activating prodrugs to their active forms. Anti-cancer agents show a wide variation between individuals in response, owing partly to pharmacokinetic variability. See Scipture et al., Lancet Oncology 6:780-789 (2005). The most important site of metabolism mediated by cytochrome P450 is the liver, where these enzymes are ubiquitously expressed. There is also evidence that metabolism occurs within tumors and that the presence of these enzymes within tumors can have desirable or adverse effect on the efficacy of chemotherapeutic agents, depending on the isoform present and the cytotoxic agent given. Thus, developing anti-tumor agents that have favorable drug metabolism profiles is also a goal in drug discovery.
Accordingly, there is a great need to develop compounds useful as inhibitors of c-Met protein kinase receptor. In particular, preferred compounds should have high affinity to the c-Met receptor and show functional activity as antagonists, while showing little affinity for other kinase receptors. Furthermore, it is desirable to provide c-Met receptor antagonists that have little or no hERG binding and favorable pharmacokinetic/pharmacodynamic profiles.